European Heart Journal (2025) 00, 1–13 STATE OF THE ART REVIEW

https://doi.org/10.1093/eurheartj/ehaf167 Diabetes and metabolic disorders

Cardiovascular disease in chronic

kidney disease

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Katharina Marx-Schütt 1, David Z. I. Cherney2, Joachim Jankowski 3
,
Kunihiro Matsushita 4, Massimo Nardone 2, and Nikolaus Marx 1,
*
1
Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen, Pauwelsstraße 30, Aachen D-52074, Aachen, Germany; 2Department of Medicine, Toronto General
Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; 3Institute for Molecular Cardiovascular Research, University Hospital, RWTH Aachen, Pauwelsstraße
30, Aachen 52074, Germany; and 4Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

Received 10 October 2024; revised 7 January 2025; accepted 5 March 2025

Graphical Abstract

Cardiovascular disease in patients with chronic kidney disease

Cardiovascular mortality Patient presentation Cardiovascular mortality

Adjusted HR
4.0 Cardiovascular disease Adjusted HR
4.0
3.0
3.0
2.0
Screening 2.0
1.5
eGFR Chronic kidney disease? UACR 1.5
1.0 (measurement of eGFR and UACR) 1.0
0.8 0.8
0 0
0 15 30 45 60 75 90 105 120 0 2.5 5 10 30 300 1000
eGFR (mL/min per 1.73m3) CKD + CVD UACR (mg/g)

CKD +
Comorbidities CKD + CAD CKD + HFrEF CKD + Afib
HFmrEF / HFpEF

Standard of
care therapy
Statin RASi SGLT2i (Semaglutide*)

ARNI instead of ACEi

Specific ASA Anticoagulation
B-Blocker Finerenone
therapy (Finerenone*) (Finerenone*)
MRA
* if type 2 diabetes

* Corresponding author. Email: nmarx@ukaachen.de

© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.
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2 Marx-Schütt et al.

Abstract

Individuals with chronic kidney disease (CKD) exhibit an increased risk for the development of cardiovascular disease (CVD) with its manifestations
coronary artery disease, stroke, heart failure, arrhythmias, and sudden cardiac death. The presence of both, CVD and CKD has a major impact on the
prognosis of patients. This association likely reflects the involvement of several pathophysiological mechanisms, including shared risk factors (e.g.
diabetes and hypertension), as well as other factors such as inflammation, anaemia, volume overload, and the presence of uraemic toxins.
Identifying and characterizing CKD is crucial for appropriate CVD risk prediction. Mitigating CVD risk in patients with CKD mandates a multidis­
ciplinary approach involving cardiologists, nephrologists, and other health care professionals. The present State-of-the-Art Review addresses the

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current understanding on the pathophysiological link between CVD and CKD, clinical implications and challenges in the treatment of these patients.
.............................................................................................................................................................................................
Keywords Chronic kidney disease • Cardiovascular disease • SGLT2 inhibitors • GLP-1 receptor agonists • Non-steroidal MRAs •
CV risk

Patients with chronic kidney disease (CKD) exhibit an elevated risk to across countries and regions, but diabetes and hypertension are consid­
develop cardiovascular disease (CVD) with its different manifestations ered as the two leading causes of CKD worldwide.7 Given these two
of coronary artery disease (CAD), stroke, heart failure (HF), or arrhyth­ factors as leading risk factors of CVD, it is not surprising that individuals
mias and sudden cardiac death. In addition, the presence of CKD has a with CKD have a higher risk of CVD compared with those without.8
major impact on the prognosis of patients with CVD, leading to an in­ Chronic kidney disease is associated with an elevated risk of many
creased morbidity and mortality if both comorbidities are present. CVD types [atherosclerotic cardiovascular disease (ASCVD), heart fail­
Therapeutic options including medical therapy as well as interventional ure (HF), aortic disease, arrhythmias, and venous thrombosis)9 and par­
treatment are often limited in patients with advanced CKD and in most ticularly with severe phenotypes (e.g. CVD mortality), as detailed
cardiovascular outcome trials (CVOTs) patients with advanced CKD below.8
have been excluded. Thus, in many patients, treatment strategies for An international consortium including data from ∼80 cohorts from
CVD need to be extrapolated from trials conducted in patients without ∼50 countries, the CKD Prognosis Consortium, has conducted a series
CKD. The current overview article addresses aspects on the diagnosis of individual-level data meta-analysis to quantify the association of the
of CKD, the pathophysiology of CVD in CKD and provides an update two key measures of CKD, eGFR, and albuminuria, with major CV out­
on CV risk reduction in CKD as well as treatment strategies in CKD comes (i.e. CAD, stroke, HF, and CV mortality).8 As shown in Figure 2,
patients with the most frequent CVD manifestations of CAD, HF, lower eGFR and higher albuminuria are associated with all CVD out­
and arrhythmias. comes, independently of traditional risk factors such as age, blood pres­
sure, and diabetes. Importantly, the associations appeared stronger for
CV mortality and HF compared with CAD and stroke.
Diagnosis and classification of CKD Several studies have reported the robust association of CKD with
the risk of developing atrial fibrillation (Afib).10–12 A US study applied
Chronic kidney disease is defined as a change in kidney structure or
2-week electrocardiogram in community-dwelling older adults and
function that has existed for >3 months with implications for
showed that CKD is also associated with Afib burden (i.e. percent
health. Chronic kidney disease stages are categorized by glomerular fil­
time with Afib).13 This study also uniquely identified other arrhythmias
tration rate (GFR) and albuminuria categories (Figure 1). The CKD
related to CKD (e.g. non-sustained ventricular tachycardia and long
Epidemiology Collaboration (CKD-EPI) has developed eGFR equations
pause). Several studies have also shown the independent association
based on measurements of creatinine and/or cystatin C. Even if an
of CKD with sudden cardiac death.14 The presence of Afib in patients
eGFR is ≥60 mL/min/1.73 m2, the presence of albuminuria or other evi­
with advanced CKD is associated with increased CV morbidity and
dence of kidney disease can define CKD. A sustained decrease in eGFR
mortality. A Dutch observational study showed that of 12 394 patients
<60 mL/min/1.73 m2 (i.e. CKD stages G3–5) is sufficient to make the
presenting as outpatients, 699 had Afib, 2752 had CKD, and 325 had
diagnosis of CKD. The most advanced stage of CKD, G5, is character­
Afib and CKD. After adjustment, patients with CKD and Afib had a
ized by an eGFR of <15 mL/min/1.73 m2. Albuminuria is an early mark­
3.0-fold increased risk of bleeding (95% CI: 2.0–4.4), a 4.2-fold increased
er of nephropathy and has a predictive value for the risk of kidney
risk of ischaemic stroke (95% CI: 3.0–6.0), and a 2.2-fold increased risk
failure as well as for CVD and all-cause mortality, regardless of eGFR.
of mortality (95% CI: 1.9–2.6) compared to people without Afib and
Measurement of the urinary albumin creatinine ratio (UACR)
without CKD.15
in spontaneously voided urine allows for efficient identification and
quantification of albuminuria.1 Of note, albuminuria measurement
can potentially provide false positive results e.g. after exercise or during
infection. CVD risk prediction in CKD
Despite a body of evidence linking CKD with elevated CVD risk, major
prediction tools used in clinical guidelines have not directly incorpo­
Epidemiology, prognosis rated CKD measures (e.g. SCORE2 and SCORE2-OP in Europe and
The prevalence of CKD is estimated to be ∼10–20% in many coun­ the Pooled Cohort Equation in the US).16,17 However, a group of ex­
tries.2–5 Approximately 5 million individuals are estimated to require perts developed an add-on tool (‘CKD Add-on’; https://ckdpcrisk.org)
renal replacement therapy (i.e. dialysis or kidney transplantation) glo­ to calibrate predicted risk according to CKD measured on top of those
bally.6 The composition of primary causes of CKD varies considerably established prediction tools.18,19 For example, a 62-year-old man in a
Cardiovascular disease in chronic kidney disease 3

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Figure 1 Current chronic kidney disease nomenclature used by KDIGO. KDIGO staging system for chronic kidney disease based on categories of
glomerular filtration rate and urinary albumin creatinine ratio. The colours represent the risk of developing a need for dialysis or other relevant out­
comes including cardiovascular disease. Green indicates low risk (and represents no chronic kidney disease if there is no structural or histological evi­
dence of kidney disease). Compared with low risk (estimated at 0.04/1000 patient-years), yellow indicates chronic kidney disease with moderately
increased risk (at least ∼5-fold), orange indicates chronic kidney disease with high risk (at least ∼20-fold), and red indicates chronic kidney disease
with very high risk (at least ∼150-fold). From1.

European moderate-risk region with no smoking history, no diabetes, from a contractile to a synthetic phenotype due to haemodynamic
systolic blood pressure (SBP) of 128 mmHg, total cholesterol of changes associated with CKD and this transition accelerates vascular
4.5 mmol/L, and high-density lipoprotein cholesterol of 1.6 mmol/L calcifications, which are notably prevalent even in children with ad­
has a 10-year predicted risk of 5.9% based on the original SCORE2. If vanced CKD.22 Moreover, dysregulation of mineral metabolism with in­
he has eGFR of 25 mL/min/1.73 m2 and ACR of 500 mg/g, with the creased phosphate as well as elevated levels of parathyroid hormone
CKD Add-on, this person’s risk is predicted to be 23%.19 and fibroblast growth factor 23 (FGF23) promote vascular but also
In the US, the American Heart Association, in collaboration with the valvular calcification.23 Although previously attributed solely to elevated
CKD Prognosis Consortium, has recently proposed a new risk predic­ calcium-phosphorus product levels, it is now understood that active
tion tool, PREVENT, to predict the risk of a composite of CVD (myo­ cellular processes also play a significant role in vascular and valvular cal­
cardial infarction, stroke, and HF) in US adults aged 30–79 years.20 This cification. All stages of CKD are associated with enhanced valvular cal­
equation uniquely includes eGFR in the primary model together with cifications: up to 99% of patients with CKD stage G5 experience
other traditional risk factors such as lipids, blood pressure, diabetes, valvular calcification compared with only 40% at CKD stage 3.24
and smoking. The equation provides an option to include information Inflammation plays a critical role in CKD. Proinflammatory mediators in­
on ACR (https://professional.heart.org/en/guidelines-and-statements/ crease as kidney function declines and these mediators exhibit direct effects
prevent-calculator). in the vasculature, contributing to endothelial dysfunction and recruitment
of inflammatory cells into the vessel wall.25 The importance of inflamma­
tion in this context is underscored by results from the CANTOS trial dem­
onstrating CVD risk reduction by inhibiting interleukin-1β (IL-1β) using
Pathophysiology of CVD in CKD canakinumab, particularly among patients with reduced eGFR.26
The development of CVD in CKD is a complex, multifactorial process Myocardial alterations in CKD manifest as pathological fibrosis and
caused by traditional risk factors such as hypertension, diabetes, or dys­ cardiac hypertrophy—hallmarks of uraemic cardiomyopathy.27
lipidaemia, as well CKD-associated factors like inflammation, oxidative Approximately one-third of CKD patients exhibit left ventricular
stress, activation of the renin-angiotensin-aldosterone-system, fluid hypertrophy (LVH), which rises to 70–80% among those with end-
overload and haemodynamic alterations, mineral and bone disorders, stage kidney disease. Left ventricular hypertrophy serves as an inde­
and accumulation of uraemic toxins as well as CKD-specific post- pendent predictor of survival across all stages of CKD. Contributing
translational modifications.21 These factors lead to characteristic mechanisms include afterload-related factors such as arterial stiffness
changes in the vasculature and in the heart. and systemic resistance leading to concentric LVH, while preload-
In the vasculature, calcification is a typical finding in CKD. Vascular related factors involve volume overload causing eccentric remodelling.28,29
smooth muscle cells in the medial layer of blood vessels can shift Myocardial fibrosis in CKD is characterized by collagen deposition
4 Marx-Schütt et al.

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Figure 2 Adjusted hazard ratios and 95% CIs (shaded areas or whisker plots) of cardiovascular mortality (top row), coronary heart disease (second
row), stroke (third row), and heart failure (bottom row) according to estimated glomerular filtration rate (left column) and albumin-to-creatinine ratio
(right column) in the combined general population and high-risk cohorts. The reference is estimated glomerular filtration rate 95 mL/min/1.73 m2 and
albumin-to-creatinine ratio 5 mg/g (diamond). Dots represent statistical significance (P < .05). *Adjustments were for age, sex, race/ethnicity, smoking,
systolic blood pressure, antihypertensive drugs, diabetes, total and high-density lipoprotein cholesterol concentrations, and albuminuria
(albumin-to-creatinine ratio or dipstick) or estimated glomerular filtration rate, as appropriate. In the analyses of estimated glomerular filtration
rate, there were 629 776 participants for cardiovascular mortality, 144 874 for coronary heart disease, 137 658 for stroke, and 105 127 for heart failure.
In the analyses of albumin-to-creatinine ratio, there were 120 148 participants for cardiovascular mortality, 91 185 for coronary heart disease, 82 646
for stroke, and 55 855 for heart failure. Figure from Matsushita et al.8
Cardiovascular disease in chronic kidney disease 5

between capillaries and cardiomyocytes, funneling into maladaptive Lipid management

ventricular hypertrophy and subsequent heart dilation. Still, the diagno­ Four studies in patients with varying degrees of CKD severity con­
sis of myocardial fibrosis in CKD e.g. by MRI is challenging and is so far firmed the safety of intensive LDL-C lowering with statins alone (ator­
not included in treatment decisions. vastatin, rosuvastatin, fluvastatin) or with statin in combination with
Overall, various mediators and mechanisms contribute to the devel­ ezetimibe (simvastatin) and demonstrated a reduction of serious ath­
opment and progression of CVD in patients with CKD and a complex erosclerotic events, but did not show a significant effect on the progres­
interaction of factors characterizes the multifaceted organ cross talk sion of CKD.37–39 In contrast, in patients on haemodialysis, neither the
between the CV system and the kidney in the setting of CKD ‘German Diabetes Dialysis Study’ (4D study)40 nor the A Study to
(Figure 3). The different pathophysiological aspects of CVD develop­ Evaluate the Use of Rosuvastatin in Subjects on Regular

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ment in individuals with CKD compared with those without are further Haemodialysis: An Assessment of Survival and Cardiovascular Events’
emphasized by the fact that recent CVOTs in this patient population (AURORA study)41 found a significant reduction in three-point
demonstrated mainly a reduction in HF-related outcomes but to a less­ MACE with atorvastatin or rosuvastatin, respectively, compared with
er extent in atherosclerosis-related endpoints. placebo. For PCSK9 inhibitors, subgroup analyses from the FOURIER
study of the PCSK9 inhibitor evolocumab showed that the
LDL-C-lowering effect is maintained in patients with CKD stage G3
Reduction of CV risk in CKD and that CV benefits are independent of baseline eGFR.39
Cardiovascular and kidney failure risk reduction in CKD includes man­ The ESC guidelines recommend LDL-C targets of <70 mg/dL for
agement of traditional risk factors and—based on more recent evi­ CKD stage G3 and LDL-C < 55 mg/dL for CKD stages G4/5 without
dence—treatment strategies with sodium–glucose cotransporter 2 dialysis in combination with at least a 50% reduction in baseline
(SGLT2) inhibitors, the non-steroidal mineralocorticoid receptor an­ LDL-C.42 Initiation of statin therapy is not recommended in patients re­
tagonist Finerenone and Glucagon-like peptide-1 receptor agonists quiring dialysis but should be continued if previously prescribed.42
(GLP-1 RAs). Kidney transplant recipients should also receive statin therapy (note
interaction with e.g. calcineurin inhibitors, e.g. rosuvastatin with tacro­
limus possible, fluvastatin with ciclosporin possible), although this is only
Risk factor management in CKD supported by limited study results.43
Management of risk factors including blood pressure lowering, glucose
as well as lipid management is mandatory to reduce CVD risk in CKD.
Cardiovascular risk reduction by SGLT2
Blood pressure management inhibitors
Arterial hypertension is a major risk factor for CVD and CKD, and Four randomized control trials have been conducted in dedicated CKD
lowering blood pressure is effective in reducing CVD as well as kid­ cohorts, designed to investigate the effect of SGLT2 inhibitors on either
ney failure risk in patients with CKD. Per 10 mmHg decrease in SBP, the kidney composite outcome of CKD progression, HF hospitaliza­
CVD risk reduction is more pronounced in patients with an initial tion, and CV and CKD death44–46 or the CV composite of urgent HF
SBP of ≥140 mmHg, but even among those with an SBP visits, HF hospitalization, and CV death.47 Treatment effects on other
<140 mmHg, further reductions can lead to decreased risks of CV endpoints were evaluated through secondary analyses. A recent
stroke and albuminuria.30 However, there is still disagreement as meta-analysis evaluated the effect of SGLT2 inhibition on a three-point
to whether SBP should be reduced to values <120 mmHg. This un­ MACE composite in 11 randomized control trials from participants
certainty has led to different blood pressure recommendations from with diabetes at high ASCVD risk, HF, and CKD.48 Across the three trial
different medical societies. The 2024 KDIGO guidelines adopted the populations (n = 78 607), SGLT2 inhibition reduced the rate of MACE
results of the SPRINT study31 and recommend lowering SBP to by 9%. In the subgroup of participants from dedicated CKD trials
<120 mmHg in CKD patients, when tolerated, using standardized of­ (CREDENCE, DAPA-CKD, EMPA-Kidney; n = 15 314), SGLT2 inhib­
fice BP measurement.1 The 2024 ESC guidelines recommend a target ition similarly lowered the incidence of MACE by 13% [HR: 0.87
SBP of 120–129 mmHg for adults with moderate to severe CKD and (95% CI: 0.77–0.98)]. This reduction in MACE was also consistent
an eGFR >30 mL/min/1.73 m2 if tolerated32; individualized blood across numerous subgroup analyses, including those stratified by estab­
pressure targets are recommended for patients with a lower eGFR lished ASCVD, diabetes status, eGFR, albuminuria, and KDIGO risk
or for kidney transplant patients. For details on BP management in classifications.48
CKD, we refer to the recently published 2024 ESC guidelines on Another meta-analysis evaluated the impact of SGLT2 inhibition on
the management of blood pressure.32 CKD progression in 13 randomized control trials from participants
with diabetes at high ASCVD risk, HF, and CKD.35 Across the three trial
populations (n = 90 409), SGLT2 inhibition demonstrated a 37% reduc­
Glucose management tion in the risk of CKD progression [HR: 0.63 (95% CI: 0.58–0.69)],
Diabetes mellitus is a strong risk factor for both CVD and CKD. Tight consistent in the subgroup from dedicated CKD trial population [HR:
glycaemic control is effective in reducing microvascular complications 0.62 (95% CI: 0.56–0.69)] and irrespective of diabetes status.35
such as diabetic nephropathy or retinopathy in patients with type 1
and type 2 diabetes, regardless of the blood glucose-lowering medica­
tion used.33,34 Personalized HbA1c targets between 6.5% and 7.5% Cardiovascular risk reduction by
(48–58 mmol/mol) are recommended for people with diabetes and non-steroidal-MRAs
CKD; in principle, the best possible HbA1c level—even <7.0% A recent study in individuals with CKD stage G3b could not demon­
(<53 mmol/mol)—should be achieved, unless this goal is achieved by strate a reduction in CV events by the steroidal MRA spironolactone
accepting hypoglycaemia.35,36 but showed an increased risk for side effects such as hyperkalaemia.49
6 Marx-Schütt et al.

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Figure 3 Organ cross talk between the kidney and the cardiovascular system in chronic kidney disease. Various mediators and mechanisms contribute
to the development and progression of cardiovascular disease in patients with chronic kidney disease and a complex interaction of factors characterizes
the multifaceted organ cross talk between the CV system and the kidney in the setting of chronic kidney disease. AGE, advanced glycation end products;
PTM, posttranslational modification.

The effect of the non-steroidal MRA finerenone on kidney and CV the incidence of HF hospitalization. The exclusion of participants
composite endpoints in adults with diabetic CKD on maximally toler­ with symptomatic HF with reduced ejection fraction (HFrEF) and
able RAS inhibitors was examined in the FIDELIO-DKD and low prevalence of participants with a history of HF (7.7%) highlights
FIGARO-DKD trials.50,51 These complementary trials, employing the efficacy for finerenone in the prevention of new-onset HF.53
similar trial designs, were subsequently pooled into the prespecified Finerenone also demonstrated a 23% lower incidence in the compos­
FIDELITY analysis, to elicit more robust estimates of finerenone effi­ ite renal endpoint of end-stage kidney disease (ESKD), sustained
cacy in terms of both kidney and CV outcomes.52 In the 13 026 CKD eGFR <15 mL/min/1.73 m2, sustained ≥57% decline in eGFR, or
participants with diabetes included in FIDELITY, finerenone demon­ CKD death [HR: 0.77 (95% CI: 0.67–0.88)]. Hyperkalaemia-related
strated a 14% reduction in the composite CV endpoint of CV death, treatment discontinuation was higher in participants receiving finere­
non-fatal MI, non-fatal stroke, or HF hospitalization [HR: 0.86 (95% none compared with placebo, with a low overall risk over 3-years of
CI: 0.76–0.98)], which was largely driven by treatment effects on follow-up (1.7% vs 0.6%).
Cardiovascular disease in chronic kidney disease 7

Since concomitant use of SGLT2 inhibitors (6.7%) and GLP1-RAs on kidney and CVD composite endpoints.70 A recent meta-analysis of
(7.2%) within the FIDELITY analysis were low, the additive benefits CVOTs with GLP-1 RA including FLOW and SELECT suggests that
of finerenone when added to more contemporary background care re­ GLP-1 RA reduce kidney disease progression in T2DM or over­
mains unclear and is the topic of ongoing trials (NCT05254002). weight/obesity regardless of CKD status.71
Despite the low number of participants on background SGLT2 inhib­ Future therapeutic approaches to reduce CV risk in individuals with
ition, secondary subset analysis of FIDELITY found that SGLT2 inhib­ CKD include anti-inflammatory strategies such as treatment with zilti­
ition, either prescribed prior to enrollment or during the trial, did vecimab, a fully human monoclonal antibody directed against IL-6 ligand,
not affect risk reduction for the CV or kidney composite with finere­ which is currently tested in the ZEUS trial in individuals with ASCVD
none,54 although a signal for an interactive treatment effect in favour and CKD (NCT05021835).

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of combined finerenone and SGLT2 inhibition on HF hospitalization Figure 4 summarizes the clinical approach for the reduction of CVD
was observed.53,54 Lastly, the reductions in the composite CV endpoint risk in patients with CVD and CKD without (Figure 4A) and with type 2
were similar in participants with or without pre-existing ASCVD, dem­ diabetes (Figure 4B).
onstrating that finerenone is an important ‘primary and secondary pre­
ventive’ therapy in diabetic CKD,55 and across the spectrum of baseline
eGFR and UACR.56 The ongoing CONFIDENCE trial is investigating
whether dual therapy with finerenone and an sodium–glucose Treatment of coronary artery
co-transporter-2 inhibitor is superior to either agent alone on relative disease in CKD
change in UACR.57
An important consideration is that efficacy of finerenone for the Medical therapy for ACS and CCS in
treatment of non-diabetic CKD is not yet known. The ongoing phase patients with CKD
III FIND-CKD trial (NCT05047263) aims to evaluate finerenone on According to current guidelines, drug therapy in patients with acute
the primary endpoint of total eGFR slope, and the secondary cardior­ coronary syndrome (ACS)72 or chronic coronary syndrome (CCS)73
enal composite endpoint of ESKD, sustained eGFR <15 mL/min/ with CKD should not differ from therapy in non-CKD patients, but ren­
1.73 m2, sustained ≥57% decline in eGFR, HF hospitalization, or CV ally excreted drugs used in CCS should be dose adjusted for kidney
death in 1584 patients with nondiabetic CKD.58 An additional trial in function.
people with type 1 diabetes and CKD called FINE-ONE is underway
and is designed to assess the impact of finerenone on UACR.59
Revascularization for CAD
Cardiovascular risk reduction by GLP1-RA ACS
Meta-analyses of large CVOTs performed in individuals with diabetes Given the poor prognosis of patients with ACS and CKD and the fact
or obese individuals without diabetes demonstrated that GLP1-RA re­ that CKD patients are less likely to receive appropriate therapy, current
duce the rate of the three-point MACE composite of CV death, MI, or guidelines recommend that patients with ACS and CKD should be trea­
stroke by 14% [HR: 0.86 (95% CI: 0.80–0.93)].60 No treatment hetero­ ted as aggressively as patients without CKD.72
geneity was observed in secondary subgroup analyses when partici­
pants were dichotomized according to baseline eGFR above or
below 60 mL/min/1.73 m260 or across the spectrum of eGFR and CCS
UACR in pooled analyses of the SUSTAIN-6 and PIONEER-6 trials.61 The ISCHEMIA-CKD trial examined the effect of coronary revascu­
In addition, secondary analyses from these CVOTs have individually re­ larization in patients with CKD and CCS in 777 patients with eGFR
ported a lower incidence of composite kidney outcomes, which was <30 mL/min/1.73 m2 and moderate to severe myocardial ischae­
largely driven by the reduction in macroalbuminuria progression, rather mia.74 Patients were randomized to early angiography and revascu­
than worsening eGFR or ESKD due to low event rates in non-CKD dia­ larization [either by percutaneous coronary intervention (PCI) or
betic populations.62–66 coronary bypass surgery] in addition to optimal medical therapy or
The FLOW trial was the first dedicated kidney outcome trial enrol­ to optimal medical therapy only. During a mean follow-up of 2.2
ling 3534 adults with diabetic CKD.67 Compared with placebo, sema­ years, there was no difference between the two study groups in
glutide led to a 24% lower incidence of the primary renal composite the combined primary endpoint of death from any cause or non-fatal
endpoint of kidney failure, sustained 50% decline in eGFR, or CV or myocardial infarction nor in all-cause mortality or CV mortality.
CKD death [HR: 0.76 (95% CI: 0.66–0.88)]. Further, an 18% relative Strokes were more frequent in the invasive group [22 vs 6 events;
risk reduction in the three-point MACE was also observed [HR: 0.82 HR: 3.76 (95% CI: 1.52–9.32)], as was kidney failure requiring dialysis
(95% CI: 0.68–0.98)]. These CVD risk reductions aligned with observa­ (36 vs 29 events; P = 0.14). There was no difference in
tions from a non-CKD cohort at high CVD risk from the SELECT trial, procedure-related acute kidney injury (7.8% vs 5.4%; P = 0.26), but
which included non-diabetic individuals with overweight/obesity. In the median time to dialysis initiation was shorter in the invasive group
SELECT, a 20% risk reduction in the three-point MACE was re­ (6 months vs 18.2 months).74 There was no difference in primary
ported.68 Secondary analyses of the FLOW trial also demonstrated outcome between the invasively and conservatively treated groups
that semaglutide lowered the risk of HF events or CVD death by in patients listed for kidney transplantation [25% of all participants;
17%, irrespective of HF history at baseline, with no treatment hetero­ HR: 0.91 (95% CI: 0.54–1.54)] compared to unlisted [HR: 1.03
geneity in subgroup analyses by KDIGO risk classification.69 Lastly, con­ (95% CI: 0.78–1.37)] patients. These results do not support routine
comitant use of SGLT2 inhibitors was relatively low in the FLOW trial coronary angiography or revascularization in patients with advanced
(15.6%) with secondary subset analyses demonstrating that concomi­ CKD and CCS before inclusion on the waiting list for kidney
tant SGLT2 inhibitor use did not alter treatment effects of semaglutide transplantation.
8 Marx-Schütt et al.

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Figure 4 Clinical approach for the management of cardiovascular disease in patients with chronic kidney disease not on haemodialysis. A, All patients
with cardiovascular disease need screening for the presence of chronic kidney disease by measurement of estimated glomerular filtration rate (eGFR) as
well as urine albumin-to-creatinine ratio (UACR) assessment in the spot urine. Patients with both cardiovascular disease and chronic kidney disease
benefit from standard treatment with a statin, RAS inhibition (angiotensin-converting enzyme inhibitor or angiotensin-II receptor blocker) as well as
a sodium–glucose co-transporter-2 inhibitor on top of stringent blood pressure control with a systolic blood pressure < 130 mmHg. In addition, de­
pending on the cardiovascular disease manifestation (coronary artery disease, heart failure with reduced ejection fraction (HFrEF), heart failure with
mildly reduced ejection fraction/preserved ejection fraction (HFmrEF/HFpEF), or atrial fibrillation, additional specific therapies need to be implemen­
ted). B, All patients with cardiovascular disease and type 2 diabetes need screening for the presence of chronic kidney disease by measurement of eGFR
as well as UACR assessment in the spot urine. Patients with cardiovascular disease, type 2 diabetes and chronic kidney disease benefit from standard
treatment with a statin, semaglutide, RAS inhibition (angiotensin-converting enzyme inhibitor or angiotensin-II receptor blocker) as well as an sodium–
glucose cotransporter 2 inhibitor on top of stringent blood pressure control (systolic blood pressure < 130 mmHg). In addition, depending on the
cardiovascular disease manifestation (chronic kidney disease, HFrEF, HFmrEF/HFpEF, or atrial fibrillation, additional specific therapies need to be im­
plemented. Afib, atrial fibrillation; ASA, acetylsalicylic acid; B-blocker, beta-blocker; MRA, mineralocorticoid-receptor antagonist.

Treatment of HF in CKD without RAS-inhibition.78 Interestingly, registry data from Japan (n =

6965, eGFR 10–60 mL/min/1.73 m2) suggests that permanent discon­
Treatment of HFrEF in CKD tinuation of an ACE-I or ARB due to side effects was associated with
Based on the data of large CVOTs in patients with HFrEF, current treat­ an increased risk of kidney outcomes and mortality.79
ment strategies are based on 4 foundational therapies: angiotensin re­
ceptor–neprilysin inhibitor (ARNI)/ACE-I, beta blockers, MRAs, and
SGLT2 inhibitors. All these agents have a class I recommendation in cur­
ARNI
rent European and American guidelines for the reduction of CV mor­ The ARNI Sacubitril Valsartan was examined in a large outcome trial in
bidity and mortality. Patients with CKD Stages G4 and 5 were excluded HFrEF patients compared with the ACE-I enalapril. In patients with
in many of these guideline-relevant HF studies and thus recommenda­ CKD stage G1 to 3, the ARNI was effective in significantly reducing
tions for this patient population must be extrapolated from data in the primary endpoint of CV death and HF hospitalization. This benefit
HFrEF patients without advanced CKD. According to current guide­ was also observed in patients with an eGFR of 30–60 mL/min/1.73 m280
lines, all 4 prognosis-improving drugs should ideally be implemented suggesting that ARNIs are effective in HFrEF in CKD Stage G1–3.
simultaneously and uptitrated within 6 weeks while monitoring kidney Reliable evidence for the use of ARNIs in CKD Stage G4–5 is missing
function and potassium,75,76 based on data from the Safety, Tolerability and these drugs may be used at reduced doses in an individualized ap­
and Efficacy of Rapid Optimization, Helped by NT-proBNP testinG, of proach considering potential side effects such as hypotension as well as
Heart Failure Therapies (STRONG-AF) study.77 an increase in potassium and/or creatinine values.

ACE inhibitors Beta blockers

Angiotensin-converting enzyme inhibitor were the first class of drugs Various clinical trials have demonstrated a reduction in morbidity and
that demonstrated a reduction in mortality and morbidity in patients mortality in patients treated with beta blockers in HFrEF including patients
with HFrEF but in these trials only patients with CKD stage G1 to 3 at CKD Stage G3. A meta-analysis of 6 studies analyzing the effect of beta
were included. Data derived from the Swedish Heart Failure Registry blocker therapy in HFrEF and CKD Stages G3–5 suggest positive effects
including 2410 patients with HFrEF and CKD (serum creatinine 2,5 for patients with advanced CKD.81 Moreover, a large retrospective ana­
or above or creatinine clearance <30 mL/min/1.73 m2) with or without lysis from Canada demonstrated that beta blocker therapy, with bisopro­
RAS-inhibition suggest that overall mortality after 1 year was significant­ lol, carvedilol, and metoprolol was associated with reduced mortality in
ly lower in patients receiving RAS-inhibition compared to patients patients with HF in CKD including patients with CKD Stage G4.82,83
Cardiovascular disease in chronic kidney disease 9

Mineralocorticoid receptor antagonists combined primary endpoint of total (first and recurrent HF events)
Mineralocorticoid receptor antagonists, such as spironolactone and and CV deaths; these results were mainly driven by a significant reduc­
eplerenone, have been shown to be effective in reducing mortality tion in the total number of HF exacerbations (HR: 0.82; 95% CI: 0.71–
and HF hospitalization in patients with HFrEF. However, only patients 0.94; P = .006). The reduction in CV death was not significant. There
with CKD Stages G1–3 were included in these studies.84,85 In the was no difference between the finerenone and placebo groups in all-
RALES study, spironolactone showed a comparable risk reduction cause mortality or a composite kidney endpoint. Serious adverse events
for all-cause mortality and the combined endpoint of all-cause mortality were comparable in both groups (finerenone: 38.7%; placebo: 40.5%).
and HF hospitalization in patients with impaired compared to patients Finerenone increased the risk of investigator-reported hyperkalaemia
with normal kidney function. However, there was an increased risk of (9.7% vs 4.2%) but decreased the risk of hypokalaemia (4.4% vs

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hyperkalaemia and worsening kidney function in patients with CKD.86 9.7%). Forty-eight percent of patients in this study had an eGFR <
Similar efficacy was shown in a secondary analysis of the 60 mL/min/1.73 m2; there was no significant difference for the
EMPHASIS-HF trial in patients with an eGFR of 30 to 60 mL/min/ primary endpoint in the subgroups with and without CKD.93
1.73 m2 for eplerenone in reducing CV death or HF hospitalization, re­ FINEHEART, a prespecified analysis of FIDELIO-CKD, FIGARO-
gardless of kidney function but with an increased risk of CKD, and FINEARTS-HF showed consistent benefits of finerenone
hyperkalaemia.87 on cardio-kidney outcomes in patients with a high burden of
cardio-kidney-metabolic conditions.94
SGLT2 inhibitors
Two large CVOTs in patients with HFrEF with or without diabetes Management of atrial fibrillation in
showed that dapagliflozin88 or empagliflozin89 significantly reduced
the combined endpoint of CV death or HF hospitalization compared CKD
with placebo. The results were driven by a significant reduction in HF Key aspects in the management of Afib include the avoidance of stroke
hospitalization and a non-significant reduction in CV deaths. In addition, and thromboembolism as well as the reduction of symptoms by rate or
these SGLT2 inhibitors have been shown to reduce kidney endpoints rhythm control.95
and worsening nephropathy. As these studies included patients with
eGFRs as low as 30 mL/min/1.73 m2 (DAPA-HF) or 20 mL/min/
1.73 m2 (EMPEROR-Reduced), these agents appear to be effective in Anticoagulation for Afib and CKD
HFrEF patients with CKD Stages G3 and 4. Scores for assessing the risk of thromboembolic events or bleeding
have not been validated for higher-grade CKD, and the currently
most frequently used CHA2DS2-VA score does not include eGFR or
Diuretics
albuminuria despite the fact that individuals with CKD exhibit an ele­
Diuretics are recommended in patients with HFrEF with signs and/or
vated risk for both thromboembolism and bleeding.96 There are no
symptoms of congestion to alleviate HF symptoms, improve exercise
published, dedicated randomized trials on the clinical risks and benefits
capacity, and reduce HF hospitalizations.75 Diuretics are effective in pa­
of anticoagulation in patients with advanced CKD. Observational stud­
tients with HFrEF and CKD, but there are no specific endpoint data for
ies suggest that vitamin K antagonist treatment with warfarin reduces
patients with CKD. A recent consensus document from the HF
the relative risk of ischaemic stroke or systemic embolism in Afib and
Association of the European Society of Cardiology suggests a practical
CKD Stage G3 by 76%.97 In contrast, the effect of warfarin for stroke
approach for initiation and uptitration of multilevel, guideline-directed
prevention in dialysis patients is controversial due to the increased risk
medical therapy for different levels of eGFR in patients with HFrEF90
of bleeding. In addition, a meta-analysis in a population of stroke pa­
(see Figure 5).
tients showed that the relative frequency of haemorrhagic strokes in­
creases with decreasing kidney function.98
Treatment of heart failure with mildly A meta-analysis of six randomized controlled trials and 19 observa­
reduced or preserved ejection fraction tional studies suggest that direct oral anti-coagulants (DOACs) are as­
sociated with better efficacy in early CKD compared with vitamin K
(HFmrEF; HFpEF)
antagonists and appear to be associated with a better safety profile in
In patients with HFmrEF/HFpEF (left ventricular ejection fraction
advanced CKD Stages G4/5.99 Data from three small, randomized trials
≥40%), the CVOTs EMPEROR-preserved91 and DELIVER92 de­
comparing DOACs vs vitamin K antagonists are now available for
monstrated a significant reduction combined endpoint of HF hospi­
haemodialysis patients, indicating an acceptable safety profile for the
talization or CV with the SGLT2 inhibitors empagliflozin or
DOACs apixaban and rivaroxaban.99–101 Of note, due to partial kidney
dapagliflozin, respectively, compared with placebo. Both trials en­
excretion, the dose of DOACs should be adjusted in patients with ad­
rolled patients with an eGFR down to 20 mL/min/1.73 m2
vanced CKD.
(EMPEROR-preserved) and 25 mL/min/1.73 m2 (DELIVER). In pre­
If there are contraindications to antithrombotic therapy, atrial ap­
specified subgroup analyses, no significant difference was
pendage occlusion can be a treatment option with registry data suggest­
found between patients with eGFR <60 mL/min/1.73 m2 and
ing an acceptable safety profile for the procedure in higher-grade
eGFR ≥60 mL/min/1.73 m2, suggesting that patients with
CKD.102
HFmrEF/HFpEF and CKD benefit from treatment with one of these
SGLT2 inhibitors.
The FINEARTS-HF study investigated the efficacy and safety of finer­ Rhythm vs rate control
enone in patients with HF and LVEF ≥ 40% including patients with an A recent meta-analysis demonstrated a 2.3-fold increased risk of recur­
eGFR down to 25 mL/min/1.73 m2. Over a median period of 32 rence of Afib after catheter ablation in individuals with CKD compared
months, finerenone led to a significant 16% relative reduction of the with those without CKD.103
10 Marx-Schütt et al.

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Figure 5 Renal-based approach to initiation and titrating of multilevel guideline-directed medical therapy. Proposed flowchart for titrating guideline-
directed medical therapy in the setting of chronic kidney disease. During titration the lower threshold of blood pressure should be individualized based
on the presence of activity limiting hypotension rather than pure blood pressure values itself. ACE-I, angiotensin-converting enzyme inhibitor; ARNI,
angiotensin receptor–neprilysin inhibitor; AV, atrioventricular; BP, blood pressure; Creat, creatinine; ECG, electrocardiogram; eGFR, estimated glom­
erular filtration rate; HR, heart rate; ISDN, isosorbide dinitrate; K, potassium; MRA, mineralocorticoid receptor antagonist; RAASi, renin–angiotensin–
aldosterone system inhibitor; SBP, systolic blood pressure; SGLT2-i, sodium–glucose cotransporter 2 inhibitor. From Mullens et al.90

Concluding key messages for the prognosis as well as the implementation of additional CVD risk redu­
cing therapies.
clinician for the management of
CVD in CKD
CV risk reduction in patients with CVD and
Screening of all patients with CVD for the CKD
presence of CKD Patients with CVD and CKD should receive the following standard
All patients with CVD should be screened for the presence of CKD by therapy to reduce CVD risk: stringent blood pressure control (SBP
assessing eGFR defined by CKD-EPI and UACR in the spot urine since < 130 mmHg), statin therapy, RASi with ACE-I or ARBs, as well as
the presence of both comorbidities has a major impact on the SGLT2 inhibitor treatment. In patients with CVD, CKD, and type 2
Cardiovascular disease in chronic kidney disease 11

diabetes, additional therapy with finerenone and semaglutide is indi­ Canadian Institutes of Health Research-Kidney Foundation of Canada
cated to further reduce the risk of CVD and kidney failure. Team Grant.

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